1. Field of the Invention
This invention comprises a process and apparatus (device)f and the use thereof for delivering to a location of choice relatively precise, preselected quantities of a material, most preferably initially in the form of a mixture of a relatively larger quantity of gas and a relatively smaller quantity of liquid in the form of microdrops, submicrodrops or a single micrdrop to a location of choice. The liquid is preferably a drug and most preferably an ophthalmic drug. Alternatively, the mixture can be one of powder in such gas.
There is a need for a practical, patient-friendly system for delivering extremely small e.g. microliter and smaller volumes of medicaments accurately to parts of the mammalian body. This is especially the case in the field of ophthalmology. However, ordinarily a single drop of current ophthalmic preparations gravity-delivered by the patient contains far more volume than the preocular tear film can hold. The excess volume delivered is either drained via the nasolacrimal drainage system, making it available for undesired systemic absorption, or lost as waste over the eyelid margin. However, even though attempts have been made to develop reliable and practical small volume delivery systems for the ocular surface, these have all been unsuccessful.
2. Advantages of the Invention
In a preferred embodiment of the delivery system, the fluid initially prior to delivery exists as microdroplets of liquid in conveying gas, which microdroplets are conveyed as one form of microdroplet or another over a relatively small distance in the atmosphere. It has also been discovered as part of this invention that the viscosity of the liquid to be conveyed affects the physical form of the delivered liquid. Usually, the more viscous the fluid, the fewer the number of microdrops. Moreover the apparatus of this invention can be modified into a host of different embodiments so that any chosen embodiment according to the principles of the inventive concepts described herein will deliver liquid in the form desired to a target of choice.
3. Summary of Choices for Application of the Invention
It has been discovered and forms the core of this invention that the total amount of liquid micro droplets chosen to be delivered to a given location, (be it one relatively large droplet or a combination of relatively small droplets) is dependent on a certain preselected volume and pressure of gas which controls the velocity of working or delivering gas. Thus, first a choice is made as to the amount of fluid in a droplet or droplets is to be delivered to a location. Then an amount of gas and the velocity of delivery is chosen in accordance with the principles of this invention that will permit that amount of fluid in that physical droplet form to be so delivered. This relationship between chosen amount of delivery fluid (the conveying fluid such as gas that is delivered under pressure and entrains the liquid to be delivered) has been defined in mathematical relationships in novel and unobvious mathematical expressions that have been developed by the inventors and form a part of the invention as described herein.
In addition to the inventive process several apparatus embodiments have been developed as part of this overall invention. These embodiments are also sometimes referred to herein as devices and are novel and unobvious in themselves. In general, the devices employ novel and unobvious pump means. These are unobvious inventive modifications of eductor pumps or venturi configurations adapted to perform as a pump. The pump embodiments of this invention comprise physical entrainment means, as means for delivering a preselected quantity of liquid of choice to a preselected quantity of gas in a conduit moving with a preselected velocity to be delivered to a target, as for example as a microdrop or as microdroplets.
5. Preferred Aspects of the Invention
The present invention in its most preferred aspect concerns a system (process and apparatuses) for delivery of exceptionally small predetermined volumes (i.e. microvolumes or submicrovolumes) in the form of microdrops or a microdrop of liquid materials to the eye, nose or other parts of the animal, preferably the mammalian body, particularly the human species thereof under circumstances wherein the total amount received is preferably 1 to 10 microliters of liquid.
6. The Preferred Apparatus Has Particular Utility in Ophthalmic Applications
The preferred apparatus of the invention has particular utility in patient self-treating of his or her eye(s) with predetermined microvolumes if liquids that may incorporate micro quantities of drugs (total volume is preferably from 1 to 10 microliters) in a reproducible and reliable manner without uncomfortable eye impact and irrespective of patient blinking. The inventive apparatus can also be small enough to be easily handled by a patient.
7. The Invention Has Utility in Other than Ophthalmic Applications
The invention also has utility in other environments, where delivery of predetermined micro or submicro quantities, sch as microvolume drops or droplets is desired. Examples would include delivery of various components for microchip manufacture and other nonmedical applications. It can also be used in vetinarinary applications. The invention can be used under very high temperatures. Moreover, it is suitable for delivery of drugs and other materials in powder form. The impact power of the apparatus can be used to power various weapons and to propel liquid directly into an environment such as the skin. It can be successfully utilized where exceptionally small quantities of materials must be delivered on a site specific manner.
8. The Apparatus of the Invention Meets all the Criterial of Generally Accepted as Necessary for Patient-Friendliness By the Ophthalmic Discipline
An especially preferred application of the process and apparatus of this invention is the delivery of micro or submicro quantities of drugs in a patient-friendly mode to the eye. In this environment, some very important medical criteria can be met by the invention. These criteria have been known to the art, but have not been achievable by any practical technique of the art. These criteria include:
1. delivery of the drug to the eye in total quantities of less than 30 ul PA1 2. delivery of the drug to the eye in droplets of less than 20 ul and as small as (1) one nanoliter PA1 3. delivery of the drug to the eye without excess force or impact to the eye. PA1 4. delivery of the drug to the eye without any factors that would cause flinching, blinking or reflex tearing PA1 5. delivery of the drug to the eye in a small delivered pattern of from 0.1 to 0.5 cm in diameter. PA1 6. drugs for delivery are in small containers easily handled by patients PA1 7. drugs for delivery are in a container that will deliver drug dosage accurately to the eye PA1 8. There is little variability of the quantity of material that is delivered in subsequent sequences. (The term "drug" includes fluids, such as liquids, powders, gels and combinations thereof) PA1 10. The invention overcomes the problem of delivery of excessive amounts of drug to the eye PA1 a) A very small quantity (micro or submicro range) of material such as a liquid can be delivered by mixing it in an inventive manner with a conveying gas PA1 b) That the use of a select pressurized gas stream with a special means to reduce the pressure in a local area of space is a useful method for delivery of small volumes or quantities. PA1 c) That contolled gas entrainment is a useful method for the delivery of small quantities of liquids or powders. PA1 d) That the repeatability in terms of a repeatable quantity of materials of a gas entrainment delivery system is enhanced by increasing the head pressure. PA1 e) it is a spray can with an internal bag to hold the liquid and does not use gas flow to control the delivery of the liquid. PA1 f) the metering is performed by controlling the time duration of the release of the fluid PA1 g) it does not teach any of the above points (a-d) that we teach. PA1 h) it is a premeasured unit dose device PA1 i) it does not teach any of the above points that are important to the instant invention. PA1 The first selection is the quantity of material such as a liquid (drug) desired to be delivered to a target such as the human eye. PA1 The second selection is the quantity i.e. volume of gas necessary to entrain and convey such material, i.e. liquid to a selected target, (ordinary air and other gases even more inert can be used). PA1 The third selection is the pressure under which such gas needs to be placed in order to achieve the desired velocity necessary for both conveying such gas past a reservoir containing liquid to be delivered and also having sufficient velocity after entraining (inducing) the desired quantity of liquid to convey such liquid to the selected target, PA1 The fourth selection is the gas/liquid entrainment (induction) mode by which the proper quantity of liquid is placed in the gas stream. The two modes that have been found to be most effective are the eductor pump mode and an inventinve modification of a venturi called a modified venturi to result in a pump. Both modifications have been invented by the inventors hereof and form important features of this invention. PA1 The fifth selection is the dimensions of the device within which the patient-friendly process of the invention can be achieved. The device must be relatively small, say occupying from 0.20 to 20, most preferably 3 to 10 cubic inches. It can be any shape but it is preferred that it be cylindrical. PA1 The sixth selection is the means for gas propulsion. It can be a spring powered piston for compressing the gas and forcing it through a conduit. It can be an exterior source of gas under pressure such as from a CO.sub.2 cartridge PA1 The seventh selection is the cross-sectional size of the conduits that are used to convey the propelling gas through a pump system, where it entrains a desired preselected amount of liquid and then to the outside of the device. PA1 The eighth selection is the cross-sectional diameter and length of the conduits that are needed to convey a preselected amount of liquid to the conveying gas. PA1 The ninth selection is the location and design of a reservoir for material (liquid or powder) within or without the device for the material source. PA1 The tenth selection is the location and design of a reservoir for the gas propulsion source either within or without the main body of the device. PA1 The eleventh selection is the location and configuration of the conduits referred to above within the main body of the container PA1 The twelfth selection is the release mode that initiates the sequence of events commencing with the pressurized gas flowing through a conduit on the way to one of the pumping means mentioned above. PA1 The thirteenth selection is optional. It involves providing in the modified venturi mode valving means for reducing pressure on the liquid reservoir at an appropriate point in the inventive sequence thereby permitting both means for achieving the predetermined liquid to be entrained as well as allowing gas free of liquid to exit from the container to purge the exit orifice of any residual liquid so as to avoid residual material such as liquid for the next delivery cycle. PA1 The fourteenth selection is that which involves the type of mixing of material in the pump means with respect to the formation of a about a single drop to formation of many even smaller droplets. PA1 The fifteenth selection is the ratio of gas to liquid the mixing ratio which must be predetermined in accordance with the amount of material desired to be delivered. It is in the range of the ratio of 3000 to 1000 to 1 by volume. The relative size of the conduits relates to the determination to the amount of gas to be used to achieve delivery of a given quantity of liquid. PA1 The sixteenth selection is the pitch of the helix of the twist ring. The pitch must be sufficient that the spring can be compressed the desired amount without an unreasonable amount of turning. Furthermore, the pitch must not be so great that the twist ring is hard to turn. In the most preferred embodiment the use of 1/2 to 1 full turn to fully compress the spring provides a typical range for the twist ring. The vertical displacement of the piston from this twist is typically 0.1" to 0.3". PA1 The seventeenth selection is that the material reservoir size must be selected relative to the total amount of conveyed air used. The reservoir size must not be so large that the reservoir cannot be sufficiently pressurized by the action of the piston to provide reasonably accurate delivery. In some cases, some empty space above the reservoir material is desirable to prevent the change in volume from the evacuation of the material from the reservoir from changing the delivery of the material. For 1 ml of total air displacement, the reservoir volume should be in the range of 1 to 5 ml. PA1 The eighteenth selection is to choose the length of the feeder tube for the pump. If a fixed amount of fluid is desired, with a very low variability, then a longer feeder tube is desired. PA1 The nineteenth selection is the overall size of the device. The device must typically fit in the palm of one hand. It must also be light enough that it can be easily manipulated so that the device can be aimed accurately and the material can be delivered to the desired area.
Thus, as will be discussed herein, excessive drug (more than 10 ul) in the eye is exceptionably undesirable. Mircopiptettes are known to deliver less than 30 ul quantities in single droplet form. Spray atomizers are known to deliver microliter droplets but in greater total liquid quantity than desired. Moreover, it is not known in the art how to design spray atomizers to deliver any of a preselected range of fluid quantities, especially in quantities less than 30 ul. Spray atomizers using either eductor pumps or direct liquid pressure are designed to deliver a gross and variable amount of spray in empirically determined and highly variable amounts, with no knowledge that there is a determinable correlation between the amount of fluid delivered and the amount of gas to entrain and transmit the fluid. They are also inherently flawed because of the high variability in the quantity of material delivered. It is very important that the same amount of drug be delivered on each sequential drug delivery step in the case of ophthalmic and other medical uses.
2. Related Art
The art has long recognized the need for a practical, patient-utilizable (patient-friendly) device for delivering microvolumes (often measured as microliters) of medicaments accurately to parts of the human body and by implication to other mammals. This is especially the case in the field of human ophthalmology.
The eye contains a preocular tear film to which medication may be applied. The current state of the art is such that the smallest single drop (20 to 50 ul) of ophthalmic preparations self-administered by a patient in a device of the present art delivers far more volume than such preocular tear film can hold. (An exception to this might appear to be the laboratory micropipette, but it is totally unsuitable for individual patient self-treatment, especially on a chronic basis.)
When such excess volume is delivered to the eye, it is either drained through the nasolacrimal drainage system or lost as waste over the eyelid margin. In the drainage mode, the excess may be made available to the body via systemic absorption by the body. This is generally undesirable and can produce serious side effects. Nevertheless, a reliable and practical microvolume or submicrovolume delivery system, easily, usable by patients (patient friendly) had not hitherto been developed before the instant invention. Moreover the apparatus of the invention is easily and inexpensively manufactured and relatively simple but elegant in design. It can also deliver repeatably uniform units of liquids or powders.
The lacrimal differences (both dynamic and correlatively pharmacokinetic) between large &gt;30 ul) and small (&lt;30 ul and as low as 5 ul) volumes of drugs instilled in the eye have been well characterized. Studies in rabbits have determined that the rate of drainage from the nasolacrimal; system is directly proportional to the instilled volume of liquid in the preocular tear film of the eye (Chrai et al., 1973).
The normal preocular tear volume is 6.8 to 7.9 or about 7.5 ul. Under highly controlled laboratory conditions permitting normal blinking, the preocular tear volume can be transiently expanded by another 10 ul without overflow (Chrai et al., 1973). Additionally, induced reflex blinking increases the rate of drug loss as the instilled volume increases. Larger volumes of liquid result in a greater rate of preocular drug loss. Increased instilled drug volume results in both increased drainage of drug via responses from reflex tearing, thus further diluting the drug with stimulated tears. This means the rate of drug loss actually increases as the volume of drug instilled increases (Chrai et al., 1974). Fractional ocular absorption also increases with decreasing instilled volume which is an inherent advantage of the instant invention.
Studies in rabbits using micropipettes to deliver ophthalmologically-active drugs suggest the desirability of delivering microvolumes or submicrovolumes to the eye in order to minimize systemic effects and maximize local ocular effects.
The most relevant devices known to the prior art that deliver micro quantities of fluid are International application numbers PCT/GB95/01482 and PCT/GB95/02040 both filed by R. P. Scherer Corporation
The instant invention in contrast demonstrates that:
International application number PCT/GB95/01482 filed by R. P. Scherer Corporation, is not a relevant teaching for the instant invention in that:
International application number PCT/GB95/02040 filed by R. P. Scherer Corporation, is not a releant teaching for the instant invention in that
International application number PCT/GB96/03195 filed by R. P. Scherer Corporation teaches the use of a spray of fluid in gas in micro quantities. It is old in the art to use sprays as exemplified by Mistura.TM.. It is old in the art to use microvolumes of drug in eye delivery. Applicants invention resides in the fact that once it is known that sprays of micro fluids are desirable for drug delivery, particularly in the eye, that they have developed a novel, unobvious and practical process for reliably delivering repeated uniform quantities and several apparatuses for effectuating such process. The inventive apparatus produces expceptionally small patterns of droplets smaller than patterns deposited from any such procedure produced by the process or apparatus of Scherer.
Studies in rabbits using micropipettes to deliver ophthalmologically-active drugs suggest the desirability of delivering micro quantities of liquid volumes to the eye in order to minimize undesirable local and systemic effects and maximize desired local ocular effects. Pilocarpine, a cholinergic parasympathomimetic agent that is used in the treatment of glaucoma, has ocular effects including constriction of the pupil and lowering of the intraocular pressure (IOP). Unwanted systemic effects of this drug may include intestinal spasm, broncho constriction, hypotension, and decreased heart rate.
Decreasing the dose of pilocarpine administered to the eye allows equivalent absorption of pilocarpine in the aqueous humor of the eye, lowering the IOP, but decreased pilocarpine concentration in the plasma of rabbits (Patton and Francoeur, 1978; Himmelstein et al., 1978). Other studies have confirmed the existence of this dose effect regarding medication delivered to the eye. For example, Patton found that decreasing the instilled volume to the eye actually increases the fraction of pilocarpine absorbed into the eye from the preocular tear film (Patton, 1977). This process of increased fractional ocular absorption is an inherent advantage of the microvolume instillation of the instant invention. Numerous studies in humans further support the desirability of decreasing the volume of liquid pharmaceuticals delivered to the eye. However no practical and reliable apparatus has hitherto been available for this purpose.
Smaller ocular volumes allow maintenance of the desired ocular therapeutic effects while decreasing or eliminating undesired systemic and local side effects. These smaller volumes have been administered using calibrated micropipettes as delivery devices. Using clonidine, an antihypertensive agent, Petursson et al., (1984) determined that instilling small volumes of 15 ul to the eye results in separation of the desired ocular hypotensive effects from the undesired systemic hypotensive effects and equivalent decreases in intraocular pressures as compared with larger volumes.
Other authors found that changing the volume of phenylephrine administered to the eye from 32 ul to 10 ul had the same beneficial effect (pupillary dilation), while markedly decreasing systemic absorption and side effects such as increased blood pressure (Brown et. al., 1986). A study in infants using phenylephrine demonstrated that a relatively small volume (8 ul) produced equivalent ocular effects and significantly lowered systemic blood levels of phenylephrine by 50% when compared to a 30 ul dose (Brown et al., 1987). A study with healthy adult volunteers found no enhancement of pupillary constriction with macrodrop (more than 30 ul) versus microdrop (less than 30 ul)volumes of pilocarpine (File and Patton, 1980) while minimizing undesirable side effects. These studies indicate the advantages of using small microliter volumes for ocular applications; however, the problem of reproducible administration of microvolumes of drug has not been addressed by the prior art, but has been solved by the instant invention.
While these several studies have demonstrated the benefits of using small microliter volumes of ophthalmic liquids, the mode of delivery (micropipettes) described is used extensively in laboratory studies, but is not suitable for self-administration by patients, because of their length and consequent difficulty in holding and directing accurately. Thus, no methods or devices have been described in the art or which are known to commerce which can accurately and reliably deliver microvolumes in a patient-friendly mode. Moreover, the apparatuses of the invention satisfy these criteria and others, including being reliable in terms of accurate delivery quantities and are easily manufactured. In addition, they are exceptionally user-friendly, as exemplified by the fact that they can be easily manipulated by non-medical persons and patients.
Current ophthalmic patient single-droplet-gravity driven delivery systems provide liquids as macrovolume quantities, which is defined as 30 ul and larger. These systems cannot reproducibly deliver smaller quantities nor is the delivery adequately controlled so as to comply with the criteria set forth above. Micropipettes are unduly long and cannot be controlled by a patient who is self-administering the drug.
No methods or apparatuses are known in commerce, which can accurately and reliably deliver micro or submicro liter volumes, are reliable and easily manufactured, and are easily manipulated by non-medical personnel and patients. The invention of this Application accomplishes those objectives. Current single-droplet-gravity-driven delivery systems use volumes on the order of 30 ul and larger because they cannot reliably deliver smaller dosage volumes. Volumes of 30 ul or more result in a large overdose to the eye with undesired local or systemic side effects as the excess drug is absorbed into the circulatory system as described in detail above reduce effectiveness and diminsh retention time on the ocular surface. The reflex tearing and blinking that accompanies instillation of macrodrops to the eye may cause significant dilution of drug and increased drainage of the drug. Reflex tearing may be in excess of 25 ul per min. Reduced retention time caused by the activation of reflux tearing and blinking may cause the drug to be washed out and drained from the ocular surface, thus reducing preocular residence time and ocular availability. Blinking that can accompany the instillation of a 30-50 ul drop in the eye enhances liquid entry into the nasolacrimal drainage system, thereby increasing the rate of drug loss from the preocular tear film and its availability for subsequent systemic absorption.
Current ophthalmic drug delivery devices also present a substantial problem in that the tip of the medicine dropper can easily come into contact with the eye or surrounding tissue. This creates a path for contaminants including microbes to travel between the delivery device and the eye. This is due in part to the fact that patients tend to hold their heads in an awkward position, thus making it more difficult for them to judge where the dispenser bottle is being held relative to the eye, often resulting in the tip touching the eye or ocular adnexa. In addition, contact between the dispenser tip and the eye or adnexa may result in clogging of the tip with lipids, proteins, or exogenous material such as components of make-up.
Conventional ophthalmic delivery devices typically deliver a single drop by gravity of about 30 ul or more. It is easy to accidentally squeeze the dropper bottle and deliver multiple drops with this dispenser, thus doubling or tripling the dosage with concomitant systemic absorption with local ocular side effects and waste.
For ophthalmic drugs to be effective, they must be delivered with reasonable reliability to the eye. With current ocular drug delivery systems, it is possible for a patient to miss the eye completely, for example by depositing the drug on the eyelid, and to assume that the drug has been properly delivered. Thus, lack of efficacy may also be related to the shortcomings of the delivery system.
The instillation of too large a volume of liquid, 30 ul or more, to the eye may result in a number of phenomena such as described above that reduce the efficiency of drug pharmacokinetics. For example, reflex tearing results in dilution of the delivered volume, and enhances drainage into the nasolacrimal drainage system. Reflex blinking as a result of macrodrop delivery accentuates the reduction in preocular residence time, and enhances drainage through the nasolacrimal drainage system and increases the opportunity for undesired systemic absorption. Use of macrodrops may further cause discomfort, such as burning and stinging, to the user. Thus, the ability to consistently and reliably deliver volumes of liquid medicaments as small as 1 microliter, preferably 1 to 5 microliters or smaller is a desirable goal, that is achievable by the present invention.